Mesangial cell turnover in normal glomeruli is a slow and orderly process. The presence of mitogenic stimuli such as inflammation, elevated levels of certain hormones and growth factors increase mesangial cell turnover. The source(s) of proliferating mesangial cells in maintenance in the normal glomerular structure or in disease has not been determined. Since the majority of cells in adult tissues, including mesangial cells, are thought to be terminally differentiated and have lost their capacity to replicate, we postulate that proliferating mesangial cells be composed of progenitor or stem cells. We hypothesize that mesangial cell progenitors reside both in the bone marrow and in the glomerulus. We further hypothesize that mesangial progenitor cells in the bone marrow are a major source of cells involved in mesangial cell proliferation in the glomerular injury response. Our preliminary data suggests that cultured mouse mesangial cells exhibit properties of progenitor cells, including an extended replicative life span in vitro and the ability to home to glomeruli in vivo. We propose to determine if the lack of replicative senescence in these cells is due to the acquisition of genetic changes that allow them to escape cell cycle arrest. In addition, we propose to confirm the homing capacity and specificity of these cells. Our data suggest that bone marrow derived mesangial cell progenitors play an important role in mesangial cell turnover. We found that lethal irradiation eliminates both bone marrow and glomerular local mesangial cell progenitors. We will use this method to dissect the role of bone marrow and glomerular local progenitors in reconstituting the mesangial cells after snake venom induced injury. Finally, we will examine the trafficking of mesangial cell progenitors between bone marrow and glomeruli. [unreadable] [unreadable] In summary, this proposal will lead to the identification of the source(s) of normal glomerular mesangial cell progenitors, the role of bone marrow derived mesangial cell progenitors in reconstitution of the mesangium after injury, and the trafficking of mesangial cell progenitors between the bone marrow and glomeruli. [unreadable] [unreadable]